An insufficient number of tumor cells entering secondary lymphoid tissues and/or an inadequate number of immune cells migrating into tumor tissues allows tumors to escape rejection. Creating lymphoid-like structures within the tumor may ovcrcome such barriers by attracting more naive T cells and dendritic cells (DCs) to the tumor site, thereby leading to efficient tumor immunity. The development and maintenance of lymphoid structures that are required for proper immune responses depend on the activation of lymphotoxin-beta receptor (LTbetaR) on stromal cells. LIGHT is a newly identified ligand for both LTbetaR and herpes virus cntry mediator (HVEM). Interestingly, preliminary data from this laboratory indicate that LIGHT-mediated signaling via LTbetaR enhances the production of lymphoid tissue chemokines that promote the formation of lymphoid tissues, whereas signaling via HVEM by LIGHT activates T cells. It is proposed here that LIGHT expressed locally in non-lymphoid tissues enhances tumor immunity, by promoting lymphoid neogenesis via LTbetaR and by activating T cells via HVEM. To test this hypothesis and to develop potential treatment regiments, the following three aims are explored: 1) The LIGHT-mediated formation of lymphoid structure will be characterized. The cellular and molecular changes that occur inside tumor and non-tumor tissues by locally expressing LIGHT will be studied to assess the role of LIGHT in lymphoid neogenesis. 2) LIGHT receptor knockout mice (LTbetaR-/- and HVEM -/-) will be used to study the relative contribution of the two LIGHT receptors in promoting the LIGHT-mediated microenvironment. 3) To determine the requirement for draining LN, the spleen, lymphoid-like structures inside tumor tissue for the development of tumor immunity, the migratory patterns and activation status of antigen-specific T cells will be traced. The potential therapeutic effects of targeting LIGHT to tumor site will be evaluated in an established tumor model. Therefore, the proposed study will provide insight into the roles of the local expression of LIGHT in tumor immunity and various lymphoid tissues in local immunity.